Therapeutic applications of endothelin receptor antagonists are rapidly expanding in cancer and cardiovascular diseases, but there is no satisfactory method to image the endothelin receptors in vivo. The goal of this project is to develop and test a radiopharmaceutical for imaging the endothelin receptors in cancer. To achieve that goal, molecular biology and immunohistochemistry methods have been developed and applied to a limited number of tissue and cell line samples and quantitative data on receptor expression have been obtained. The first xenograft SCID mouse model with simultaneous growth of ETAR positive and ETAR negative tumors has been established. Experiments with with the nonselective endothelin receptor ligand [C-11]L-753,037 have been performed. The specific aims of the project are: 1) To investigate the expression of the ETAR (endothelin A subtype receptor) and ETBR (endothelin subtype B receptor) in cancer tissues in a systematic and quantitative fashion. The results of these experiments will help plan in vivo imaging PET studies of the ETAR receptor in patients. 2) To develop and test a specific, ETAR selective radioligand for PET applications. Radiation dosimetry and biodistribution experiments will be performed in a small animal model and the estimated radiation exposure will be extrapolated to humans. Limited pharmacological studies will be performed in small animals in vivo with PET and correlated with receptor expression determined on tissue specimens in vitro. Small animal imaging experiments will be performed in CD-1 mice and regular PET/CT imaging experiments will be perfomed in baboons to develop a tracer kinetic model. 3) To perform PET imaging of animals with tumor xenografts that express the ETAR to various degrees. SCID mice bearing a variety of tumor xenografts will be investigated with PET/CT to define the distribution pattern of the radioligand and to develop a tracer kinetic model for quantification of ligand binding. PET scan findings will be compared with in vitro studies to confirm ETAR density and occupancy. The proposed studies are designed to establish a quantitative method for in vivo imaging of the ETAR. They have the potential to improve selection of cancer patients for treatment with endothelin antagonists. [unreadable] [unreadable] [unreadable]